S213: EFFICACY AND SAFETY OF HUMANIZED VERSUS MURINIZED CD19 AND CD22 CAR-T CELL COCKTAIL THERAPY FOR REFRACTORY/RELAPSED B-CELL LYMPHOMA
Authors: L. Huang, J. Li, J. Yang, X. Zhang, M. Zhang, J. He, G. Zhang, Y. Su, W. Li, H. Wang, P. Lu
Journal: HemaSphere (2022)

Background: CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated about 50~60% of response rate in relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma. However, antigen-escape relapse has emerged as a major challenge for long-term disease control after CD19-targeted therapies. In our previous study, we described a dual-targeted of CD19 and CD22 CAR-T cell cocktail therapy, whichyielded 93.3% of complete remission (CR) rate in R/R B-cell acute lymphoblastic leukemia and could reduce the risk of CD19-negative relapse. Aims: A phase I/II clinical trial (NCT05206071) was designed to explore the safety and efficacy of CAR19/22 T-cell cocktail therapy for patients with R/R aggressive B-cell lymphoma. Methods: Eligible R/R aggressive B-cell lymphoma patients were enrolled from July 2020 toDecember 2021. All patients received fludarabine 30 mg/m2/d and cyclophosphamide 250 mg/m2/d for 3 consecutive days (day −5 to day −3) followed by cocktail CAR-T cell infusion. CAR-T-cell-related cytokine release syndrome (CRS) was graded to assess the safety. PET-CT was performed on day 28 and 3rd month to evaluate the response rate. Results: A total of 26 eligible patients received CAR19/22 cocktail infusion with a median age of 46 years old (4-75) and a median of 3 prior lines of therapies (2-5 lines). Of 26 patients, 4 were Burkitt lymphoma, 2 were follicular lymphoma (grade 3a), and the rest were diffuse large B-cell lymphoma. Besides, 7 patients were diagnosed with double-hit lymphoma and 4 patients were relapsed after previous CD19 CAR-T cell therapy. Fourteen patients received the murinized CAR-T cells at a median dose of 2.18×106/kg (1-3×106/kg) CAR19 and 1.75×106/kg (1-3×106/kg) CAR22, while 12 patients received the does of the humanized CAR-T cells consisting of 2×106/kg CAR19 and 5×105/kg CAR22. At the day 28 assessment, 12/12 (100%) patients received the humanized CAR-T cells achieved overall response, including 9/12 (75%) CR and 3/12 (25%) partial remission (PR), while the overall response rate (ORR) and CR rate of the murinized group was 85.71% (12/14) and 42.86% (6/14) respectively. Among of them, all 4 Burkitt lymphoma patients in both groups achieved CR. In 3 months evaluation, 7/10 (70%,2 cases received infusion for less than 3 months) patients in the humanized group maintained in CR, which was higher than the murinized group with CR rate of 5/14 (35.71%). (Figure 1A-B). At a median follow-up of 291 days (range, 31 to 544), patients in the humanized group had a favorable progression-free survival (PFS) than those in the murinized (1-year PFS of 67.9% vs. 26.8%), although there was no statistical significance (p=0.08) due to the limited number of patients enrolled (Figure 1E-F). Achieving CR on day 28 (HR: 0.21, 95% CI: 0.06-0.72; P=0.012) and maintaining CR till the 3rd month (HR: 0.18, 95% CI: 0.06-0.59; P=0.004) were found as independent prognostic factors associated with favorable PFS. Maintaining CR till the 3rd month (HR: 0.10, 95% CI: 0.01-0.61; P=0.012) and non-double hit (HR: 0.11, 95% CI: 0.02-0.76, P=0.024) predicted a longer overall survival (OS) (Figure 1G-L). Despite impressive CR rates wereachieved, majority of patients had mild CRS (grade 1-2) in both group. Only 2patients experienced grade 3 CRS, and 2 patients developed grade 3 neurotoxicity. Image:Summary/Conclusion: This clinical trial demonstrates promising efficacy and safety of CD19/CD22 CAR-T cocktail therapy for R/R aggressive B-cell lymphoma, and patients in the humanized group showed better results than those with murinized, although this not a randomized trial.